Polymerizable compositions and methods of use

ABSTRACT

The present invention provides compositions comprising a first component and a second component, wherein the first component includes at least two polymerizable organic monomers, and wherein the second component includes an oligomer of a polymerizable organic monomer, a plasticizer and an opacificant agent, wherein said composition polymerizes upon contact with an anionic environment. The compositions are useful for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass in an anionic environment. The composition are also useful for ablating diseased or undesired tissue by cutting off the blood supply to the tissue.

[0001] This application is a continuation-in-part of U.S. applicationSer. No. 09/577,115, filed May 23, 2000, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates generally to organic compositionsand more specifically to polymerizable compositions and methods of usetherefor.

BACKGROUND OF THE INVENTION

[0003] Research in organic polymer chemistry has led to the discovery ofa variety of biocompatible polymeric materials. One important class ofsuch materials is the cyanoacrylates. These materials have been usedsuccessfully in a variety of medical applications where traditionalmedical techniques or devices have been found wanting, such as forexample, tissue adhesives, endovascular embolic agents, and the liketissue adhesives have been in clinical endovascular use since the1970's. Liquid acrylics are extremely useful as endovascular embolicagents because of their ability to create permanent vascular occlusion.Typical complications associated with the use of cyanoacrylates forembolization occur when there is occlusion of normal arterial branchesor material penetration into critical venous outflow channels.Additionally, reflux of cyanoacrylate materials around the deliverycatheter tip can result in permanent endovascular-catheter adhesion andattempts at withdrawal the catheter can produce catheter fracture,vascular damage with resultant dissection/occlusion, or avulsion of theinvolved vascular pedicle with resultant subarachnoid hemorrhage.

[0004] Alkyl α-cyanoacrylates are a homologous series of organicmolecules which readily polymerize and can adhere to living tissues. Themethyl homolog has been used in hemeostasis and non-suture wound closuresince 1960.

[0005] Polymerization rate of alkyl α-cyanoacrylates is a function ofalkyl chain length. It has been reported that alkyl α-cyanoacrylateswith six or fewer carbon atoms in the alkyl chain polymerize rapidlyupon contact with animal tissue.

[0006] Since the advent of n-butyl-2-cyanoacrylate, there has beenlittle advancement in the science of cyanoacrylate embolization ofvascular structures such as arteriovenous malformations (AVM). Severalproperties of cyanoacrylates are advantageous for such embolizations,e.g. tissue adhesion, rapid polymerization when contacted with blood andtissue, and long-term biocompatibility. Rapid polymerization allows theliquid material to solidify in flowing blood inside arteries withoutpassing through small channels into venous structures. However, thisrapid endothermic polymerization may also release sufficient heat todamage surrounding tissue, for example, brain tissue.

[0007] Although catheter coatings have been developed to reduce the riskof inadvertent endovascular catheter fixation during embolizationprocedures. catheter-cyanoacrylate adhesion remains a problem duringintravascular embolization. Also, the level of practitioner proficiencyand the specific adhesive composition utilized play a major roles inthese events.

[0008] Accordingly, there exist s a continuing need for compositionsthat have the correct balance of polymerization rate, adhesiveness,biocompatibility, and radiopacity. The present invention describes suchcompositions.

SUMMARY OF THE INVENTION

[0009] In accordance with the present invention, there are providedcompositions including a first component and a second component, whereinthe first component includes at least two polymerizable organic monomersand wherein the second component includes an organic oligomer, aplasticizer, and an opacificant agent, wherein the total compositionpolymerizes upon contact with an anionic environment. The compositionsof the present invention are useful for filling or partially filling andoccluding, or partially occluding cavities or spaces in human or animalbodies. The invention compositions are also useful for ablating diseasedor undesired tissue or organs by blocking the blood supply to the tissueor organs.

[0010] In another aspect of the present invention, there are providedmethods for filling or partially filling and occluding or partiallyoccluding cavities or spaces in a human or animal bodies. Another aspectof the present invention provides methods for ablating diseased orundesired tissue or organs by blocking the blood supply to the tissue ororgans. Other aspects of the present invention provide methods fortreating arteriovenous malformations (AVM), methods for treating neuralaneurysms, methods for treating uterine fibroids, methods for treatingsolid tumors, methods for treating uterine leiomyoma, and methods forsterilizing female mammals.

[0011] In a still further aspect of the invention, there are providedmethods for the controlled delivery and fixation of therapeuticcompositions, chemotherapeutic compositions, radiation devices, magneticparticles, or other agents to desired location in human or animalbodies.

[0012] In yet another aspect of the invention, there are providedmethods for adhering a first section of mammalian tissue to either asecond section of mammalian tissue or a non-tissue surface.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention provides compositions including a firstcomponent and a second component, wherein the first component includesat least two polymerizable organic monomers and wherein the secondcomponent includes an organic oligomer, a plasticizer, and anopacificant agent, wherein the total composition polymerizes uponcontact with an anionic environment.

[0014] The composition is useful for filling, occluding, partiallyfilling or partially occluding an unfilled volume or space in a mass (“aspace”). In particular, the composition is useful for filling anexisting space, e.g., the lumen of a blood vessel, or the sac of ananeurysm, a space created by a transiently placed external device, e.g.,a catheter or like device, a space created by a procedure, e.g., anexcision or like procedure or implantation of an object, e.g., a stentor like device, or a space created by the composition; the compositionis also useful for adhering tissue to tissue, or adhering tissue to adevice. The composition has the property of polymerizing when it comesin contact with an anionic environment, or when it is deployed in situin an existing space, e.g., the lumen of a blood vessel, or the sac ofan aneurysm, a space created by a transiently placed external device,e.g., a catheter or like device, a space created by a procedure, e.g.,an excision or like procedure or implantation of an object, e.g., astent or like device, or a space created by the composition.

[0015] In a preferred embodiment, the composition includes alkylcyanoacrylates. In a particularly preferred embodiment, the firstcomponent of the composition includes, n-hexyl cyanoacrylate and methylcyanoacrylate or 2-hexyl cyanoacrylate and methyl cyanoacrylate.

[0016] In another preferred embodiment, the second component includes anoligomer or polymer formed from a composition of alkyl cyanoacrylatemonomer, an alkyl esterified fatty acid and an opacificant agent.

[0017] In yet another embodiment, the second component of thecomposition includes a halogenated oil. Preferred are iodinated andbrominated oils.

[0018] In a still further preferred embodiment, the first component iscomprised of two alkyl cyanoacrylate monomers, and at least oneinhibitor. A particularly preferred embodiment of the first componentincludes n-hexyl cyanoacrylate, methyl cyanoacrylate and one inhibitor.

[0019] A particularly preferred composition includes a first componentand a second component, wherein the first component includes methylcyanoacrylate, n-hexyl cyanoacrylate, hydroquinone, p-methoxyphenol, andacetic acid, and wherein the second component includes an oligomer orpolymer formed from n-hexyl cyanoacrylate monomer, an alkyl esterifiedfatty acid and an opacificant agent. In a most preferred embodiment, thealkyl esterified fatty acid is ethyl myristate and the opacificant agentis gold.

[0020] It is known to those of ordinary skill in the art that thepredictability of polymerization properties of alkyl cyanoacrylatemonomers is related to the purity of the monomers that are used. Thesepolymerization properties include but are not limited to, rate ofpolymerization and stability of the monomer during storage. Anotheradvantage of substantially pure alkyl cyanoacrylates is thatcompositions incorporating substantially pure alkyl cyanoacrylatesrequire smaller amounts of additives, e.g., inhibitors, stabilizers andthe like, to obtain a desired result that would otherwise have requiregreater amounts of the same additive.

[0021] Another embodiment of the present invention provides a method forfilling, occluding, partially filling or partially occluding an unfilledvolume or space in a mass by administering a composition of the presentinvention with an administering means, including a means for stabilizingfluid flow distal or proximal to the body space being treated, and ameans for delivering the composition to the desired body space. Anembodiment of the administering means is where the means for stabilizingfluid flow distal or proximal to the body space being treated is in afirst device, and the means for delivering the composition to thedesired body space is in a second device. An embodiment of the firstdevice includes a temporary inflatable balloon, or like structure, thatis inflated to stabilize fluid flow distal or proximal to the body spaceto be treated, and deflated for removal after some period after thecomposition has been delivered. Optionally the balloon structure may bejuxtaposed adjacent to the body space where the composition isdeposited, and inflated such that the balloon structure maintains thecomposition at the body space while the composition is polymerizing, anddeflated for removal after some period after the composition has beendelivered. An embodiment of the the second device includes a catheter,or like device for delivering and depositing the composition of thepresent invention at a desired location. Another embodiment of theadministering means is where the means for stabilizing fluid flow distalor proximal to the body space being treated, and the means fordelivering the composition to the desired body space are within a singledevice or apparatus.

[0022] The types of unfilled volumes or spaces within the scope of thepresent invention includes, but are not limited to the followinginstances.

[0023] For example, one aspect of the present invention is a method offilling, occluding, partially filling or partially occluding an existingspace, such as, a lumen of a passageway in the body, e.g., a bloodvessel, a duct, an aneurysm, or a fistula. Examples of the typestreatments covered by this method of use, include but are not limited tothe following. The present invention is useful as a method of treatingarteriovenous malformations (AVM) where the blood vessel(s) that feedthe AVM are occluded thereby cutting off the blood supply to the AVM.The present invention is useful as a method to ablate diseased orundesired tissue by cutting off the tissue's blood supply. Inparticular, the present invention is useful as a method of treating atumor having a discrete blood supply, where the blood vessel(s) thatfeed the tumor are occluded thereby cutting off the blood supply to thetumor resulting in diminished growth or death of the tumor. The presentinvention is useful as a method of preventing or mitigating thedevelopment of an aneurysm by creating a partial occlusion at a locationin the blood vessel selected to modify the fluid dynamics within thevessel to mitigate the formation or development of an aneurysm. Thepresent invention is useful as a non-surgical method of treatingsymptomatic uterine leiomyomas by embolizing/occluding the uterineartery. This method has been reported using a non alkyl cyanoacrylatecomposition in Journal of Vascular and Intervention Radiology,10:891-894, July-August 1999. The present invention is useful as amethod of sterilizing a female mammal by occluding the fallopian tubesthereby preventing the passage of the eggs from the ovaries to theuterus. The use of an occluding agent to sterilize a female mammal isdisclosed in U.S. Pat. No. 5,989,580 “Method of Sterilizing FemaleMammals”, herein incorporated by reference. The methods disclosed inthis patent can be advantageously applied using the compositions of thepresent invention, and are within the scope of the present invention.The present invention is useful for obliterating the left atrialappendage. The left atrial appendage is derived from the left wall ofthe primary atrium. It has been observed that patients with atrialfibrillation have a predilection for thrombus to form in the left atrialappendage. A review of this condition and the current status oftreatment is disclosed in the article, “Left Atrial Appendage:structure, function, and role in thromboembolism” N. M. Al-Saady, et.al. The present invention provides an advantageous method ofobliterating the left atrial appendage.

[0024] Another aspect of the present embodiment is a method of filling,occluding, partially filling or partially occluding a space created by atransiently placed external device, such as, a catheter balloon, a spacecreated by a transiently placed external device, e.g., a catheter orlike device. Examples of the types of treatments covered by this methodof use include, but are not limited to the following. The presentinvention is useful as a method of treating an aneurysm by filling thespace within the aneurysm with a composition of the present invention,where the composition polymerizes in the space within the aneurysm,thereby preventing the rupture of the aneurysm. The present method oftreatment can be practiced using an administering means, including ameans for stabilizing fluid flow distal or proximal to the body spacebeing treated, and a means for delivering the composition to the desiredbody space. An embodiment of the administering means is where the meansfor stabilizing fluid flow distal or proximal to the body space beingtreated is in a first device, and the means for delivering thecomposition to the desired body space is in a second device. Anembodiment of the first device includes a temporary inflatable balloon,or like structure, that is inflated to stabilize fluid flow distal orproximal to the body space to be treated, and deflated for removal aftersome period after the composition has been delivered. Optionally theballoon structure may be juxtaposed adjacent to the body space where thecomposition is deposited, and inflated such that the balloon structuremaintains the composition at the body space while the composition ispolymerizing, and deflated for removal after some period after thecomposition has been delivered. An embodiment of the the second deviceincludes a catheter, or like device for delivering and depositing thecomposition of the present invention at a desired location. Anotherembodiment of the administering means is where the means for stabilizingfluid flow distal or proximal to the body space being treated, and themeans for delivering the composition to the desired body space arewithin a single device or apparatus. Such apparatuses include, but arenot limited to, catheters, catheter coils, catheter wires, catheterballoons, or like devices. Many examples of such devices are known tothose of ordinary skill in the art. For example, U.S. Pat. No. 5,795,331“Balloon Catheter For Occluding Aneurysms of Branched Vessels”,incorporated herein by reference, discloses a device and methods fordelivering compositions, such as those of the present invention. U.S.Pat. No. 5,882,334 “Balloon/Delivery Catheter Assembly With AdjustableBalloon Positioning,” incorporated herein by reference, assigned toTarget Therapeutics, San Jose, Calif., and U.S. Pat. No. 6,015,424“Apparatus and Method For Vascular Embolization”, incorporated herein byreference, assigned to MicroVention, Inc., Aliso Viejo, Calif., describelike devices that can be employed in practicing the present invention.

[0025] The present invention may also be practiced following theprocedure and utilizing like devices described in Neurosurgery, Vol. 31,No. 3, September 1992, page 591 “Carotid-Cavernous Fistula Caused by aRuptured Intra-cavernous Aneurysm: Endovascular Treatment byElectrothrombosis with Detailable Coils.”

[0026] Another aspect of the present invention provides a method offilling, occluding, partially filling or partially occluding a spacecreated or resulting from a procedure, such as with the excision oftissue, or insufflation. Examples of the types of treatments covered bythis method of use include, but are not limited to, the following. Thepresent invention is useful as a method of treating or mitigatingcapillary oozing.

[0027] Another aspect of the present invention provides a method offilling, occluding, partially filling or partially occluding a spacecreated by the placement or implantation of an object, such as, amedical device. Examples of the types of uses covered by this method ofuse include, but are not limited to the following. The present inventionis useful as a method of restoring the normal fluid dynamics at theperipheral edges of a vascular stent by filling the dead spaces betweenthe stent and the lumen wall created by the implantation of the stent.

[0028] Another aspect of the present invention is a method of filling,occluding, partially filling or partially occluding a space created bythe composition itself, such as, where the composition is used as abulking agent. Examples of the types of uses covered by this method ofuse include, but are not limited to the following. For example, a methodof recreating the normal contours to skin following an adverse event,such as, physical trauma.

[0029] Another embodiment of the present invention provides a method ofaffixing therapeutics, chemotherapeutics, radiation delivery devices,gene therapy compositions to a desired location where the active agentscan be advantageously maintained in proximity to the desired location.The active agent is then release gradually as the resultant aggregatestructure from the composition of the present invention is biodegraded.Alternatively, the composition of the present invention can be modifiedto allow for a specific rate of delivery. This use is particularlybeneficial in the treatment of tumors that are ideally treated bylocalized dosages of chemotherapy or radiation. An advantage of thismethod is that the patient would not be subjected to as large of a doseof the therapeutic or radiation as would be necessary, if thetherapeutic or radiation was administered on a systemic basis.

[0030] Another embodiment of the present invention provides a method ofutilizing magnetically controlled particles embedded in a composition ofthe present invention to deploy the composition to a desired location.The use of magnetically controlled particles as medical probes isdescribed in the following references, incorporated herein in theirentirety: “Magnetic Probe for the Stereotaxic Thrombosis of IntracranialAneurysms,” Alksne, J. F., et. al, Journal of Neurology, Neurosurgeryand Psychiatry, 1967 April, 30(2):159-62; “Magnetically Controlled FocalIntravascular Thrombosis in Dogs” Alksne, J. F., et. al, Journal ofNeurosurgery, 1966 Nov, 25(5):516-25; “Thrombosis of IntracranialAneurysms—An experimental approach utilizing magnetically controllediron particles” Alksne, J. F., et. al, Radiology 1966 Feb. 86(2):342-3

[0031] Another embodiment of the present invention provides a method ofadhering, joining, connecting or affixing a first section of tissue to asecond section of tissue. Examples of the types of uses covered by thismethod of use include, but are not limited to the following. The presentinvention is useful as a method of adhering, joining, or connecting twoblood vessels, e.g., anastomoses, where blood vessels are quickly andefficiently adhered, joined or connected, under surgical conditionswithout the use of sutures or staples. The present invention is usefulas a method of treating primary wounds or wounds that require immediateintervention, such as, trauma wounds, where the compositions of thepresent invention are used to temporarily close the wound to minimizethe lost of fluids due to evaporation, and to mitigate infection.

[0032] Another embodiment of the present invention provides a method ofadhering, joining, connecting, or affixing tissue to a non-tissuesurface, such as a medical device. Examples of the types of uses coveredby this method of use include, but are not limited to the following. Thepresent invention is useful as a method of implanting or securing venousvalves, replacement heart valves, or stents at their desired location.

[0033] The aforementioned uses are possible because the compositions ofthe present invention remain in a controllable state for a period oftime in excess of 1 second after being deployed from an administrationdevice. This property allows the practitioner to incremental maneuverthe deployment of the composition to its most ideal location, eventhough the composition had been partially deployed distal to thedeployment device.

[0034] For instance, the compositions of the present invention haveadequate cohesion to maintain its continuity once it is outside of thedeployment device. Without adequate cohesion the composition would breakinto smaller aggregates dispersing into the blood flow. Additionally,the compositions of the present invention have appropriate adhesionproperties so that a deployed composition adheres to the immediatelocation where it is deployed so that the resultant aggregate of themonomer is placed where it is desired.

[0035] The compositions of the present invention have polymerizationrates, such that, the practitioner can effect the desired amount ofpenetration of the composition into a particular type of space. Acomposition that polymerizes too quickly would hinder penetration,conversely a composition that polymerizes too slowly would make itdifficult to precisely place the polymerized composition including theresultant aggregate of the monomer.

[0036] Another embodiment of the present invention provides a method forselectively creating an embolic blockage in the lumen of a blood vessel,duct, fistula or other like body passageways.

[0037] Another embodiment of the present invention provides a method oftreating arteriovenous malformation (AVM)

[0038] As used herein the terms “adhesion” or “adhesive” means thecharacteristic or tendency of a material to be attracted to the surfaceof a second material. Adhesion occurs as the result of interactionsbetween two materials. Depending on the characteristics of the secondmaterial relative to the first material, adhesion may or may not occur.For a single material, e.g., the composition of the present invention,the presence of adhesion is demonstrated by a material sticking to thewall of a lumen of blood vessel, i.e., there is adhesion between thematerial and the lumen wall. Conversely, the absence of adhesion isdemonstrated for the same material where a micro-catheter tip used todeposit the material can be removed from the material, i.e., there islittle adhesion between the material and micro-catheter tip.

[0039] As used herein the term “anionic environment” refers to an ionicenvironment in which the net charge is negative. Essentially an anionicenvironment is any aqueous system with pH>7. For example, a body fluidsuch as blood is an anionic environment.

[0040] As used herein the term “alkyl” refers to chains of carbon atomswhich can be linear or branched, saturated or unsaturated.

[0041] As used herein the term “cohesion”, “cohesive”, or “cohesivity”means the characteristic or tendency of a liquid or semi-liquid materialto maintain its integrity while being manipulated. For example, thischaracteristic is demonstrated by a material or composition remainingintact as a single mass when introduced into a stationary fluid, or afluid stream in motion, such as, blood. Lack of cohesive integrityresults in the composition breaking up into multiple smaller subunits.

[0042] As used herein the term “embolic agent” refers to a non-naturallyoccurring composition introduced into a body cavity or the lumen of ablood vessel, duct, fistula or other like body passageways for thepurpose of forming an embolic block.

[0043] As used herein the term “embolic block” or “embolic blockage” orocclusion refers to the end result from the administration of acomposition useful as an embolic agent. The resulting embolic blockmechanically blocks, totally or partially, the lumen of a blood vessel,duct, fistula or other like body passageways; or in a like manner formsan occlusion within a cavity, such as an aneurysm.

[0044] As used herein the term “alkyl esterified fatty acid” means afatty acid derivatized to form an ester functional group with an alkylmoiety, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, oroctyl. Suitable fatty acids are carboxylic acids containing from 1carbon (i.e., acetic acid) through 17 carbons atoms (i.e. stearic acid).

[0045] As used herein the term “opacificant agent” is compound orcomposition which selectively absorbs or deflects radiation making thematerial visible under x-ray, or any like imaging technique. Typicallysuch agents include, iodinated oils, and brominated oils, as well ascommercially available compositions, such as Pantopaque™, Lipiodol andEthiodol. These commercially available compositions acts as opacificantagents, and also dilute the amount of liquid monomer thereby slowing therate of polymerization. In addition certain metals, such as, gold,platinum, palladium tantalum, titanium, tungsten as well as alloys andmixtures thereof. Salts such as barium sulfate and the like, haveproperties enabling them to act as opacificant agents.

[0046] As used herein the term “polymerization retardant” means an agentthat can stop or slow down the rate of polymerization. Examples of suchagents are pure phosphoric acid, and 85% phosphoric acid. Certainopacificant agents, such as Pantopaque™, Lipiodol™ and Ethiodol™ canalso function as a polymerization retardant by diluting the amount ofliquid monomer and hence slowing polymerization rate.

[0047] As used herein the terms “a space” and “a body space” refer to anunfilled volume or cavity in a mass. Examples of such spaces, includebut are not limited by the following, an existing space within a mass,such as, the lumen of a blood vessel, the sac of an aneurysm; a spacecreated by a transiently placed external device, such as, a catheter orlike device; a space created by a procedure, such as, an excision orlike procedure; a space created by implantation of an object, such as, astent or like device; or a space created by the composition.

[0048] As used herein the term “stability” refers to the ability of amonomer component to resist degradation or polymerization afterpreparation but prior to use.

[0049] As used herein the term “inhibitor agent” refers to an agentwhich stabilizes a monomer composition by inhibiting polymerization.Within the context of the current invention, this term refers to agentsthat stabilize and inhibit polymerization by various mechanisms.

[0050] As used herein the term “deployment device” refers a device usedto deploy compositions, such as, those of the present invention.Examples of such devices, include but are not limited the devicesdisclosed in U.S. Pat. No. 5,882,334 “Balloon/delivery Catheter Assemblywith Adjustable Balloon Positioning,” incorporated herein by reference.

[0051] As used herein the term “oligomer” refers to chains ofpolymerizable monomers containing from 2 to about 20 repeating monomerunits. Such chains may be linear or branched.

[0052] The present invention is a composition formed from alkylcyanoacrylate monomeric units, such as, methyl, n-butyl, isobutyl,n-hexyl and 2-hexyl cyanoacrylate, a plasticizer, an opacificant agentand a thickening agent (i.e. an oligomer of a polymerizable monomer. Thecomposition forms into its resultant aggregate structure, i.e., anoligomer or polymer, when it comes in contact with an anionicenvironment, such as, blood or tissue. The resultant aggregatecomposition has characteristics which makes it particularly well suitedas an embolic agent.

[0053] “Plasticizers” are liquid materials which are added to solidpolymers to render such polymers flexible. To function as plasticizerssuch liquid materials must be chosen to be compatible on a molecularscale with the specific polymer being plasticized. To be useful in thepresent invention the chosen plasticizer must be biocompatible. The term“biocompatible plasticizer” refers to any material which is soluble ordispersible in alkyl cyanoacrylate, which increases the flexibility ofthe resulting polymer, and which is compatible with the implant site inthe body. Suitable plasticizers are well known in the art and includethose disclosed in U.S. Pat. Nos. 2,784,127 and 4,444,933 thedisclosures of both of which are incorporated herein by reference intheir entirety. Specific stabilizers include by way of example, but arenot limited to, alkyl esters of fatty acids such as alkyl myristates,alkyl laureates, alkyl stearates, and alkyl succinates. Otherplasticizers useful in the present invention include by way of example,but are not limited to, acetyl tri-n-butyl citrate, butyl benzylphthalate, dibutyl phthalate, diethyl phthalate, dimethyl phthalate,dioctylphthalate, n-butyryl tri-n-hexyl citrate, benzoate esters of di-and poly-hydroxy branched aliphatic compounds, tri(p-cresyl) phosphate,and the like. Preferred plasticizers for use in this invention are alkylesters of fatty acids of 12 to 18 carbon atoms independently having from1 to 6 carbon atoms in each alkyl group. A particularly preferredplasticizer is ethyl myristate.

[0054] The composition of the present invention is used by combining themonomer component and second component. Upon mixing of the components,the invention is administered into the lumen of a blood vessel, duct,fistula or other like body passageways. The characteristics of thepresent invention permit its accurate placement in the lumen. Contactwith an anionic environment, such as blood or tissue causes thecomposition to polymerize. The size of the resultant embolic blockformed is determined by the amount of composition administered.

[0055] Alternately, the first component and second component of thepresent invention can be combined and supplied as a single unit.Depending upon storage conditions and required storage stability thecompositions of the present invention may be supplied as a systemincluding separate first component and second component units or as asystem including a single combined unit.

[0056] The characteristics of the composition of the invention can bemodified for a specific purpose or environment for which the embolicagent is intended to be utilized. For example, changes in the length andisomeric configuration of the alkyl side chains can alter thebrittleness of the resultant aggregate of cyanoacrylate monomers. Alkylchains that result in the formation of smaller aggregates tend to beless brittle, while larger aggregates tend to be less flexible. Inaddition, by combining monomers with different alkyl side chains thecharacteristics of the resultant polymer can be modified to what isoptimal for a desired application.

[0057] The monomer components of the present invention are prepared fromcommercially available starting materials following procedures known tothose of ordinary skill in the art such as the procedures described inU.S. Pat. Nos. 3,728,375; 3,527,224; 3,591,676; 3,667,472; 3,995,641;4,035,334; and 4,650,826 which are hereby incorporated by reference.

[0058] In the context of the present invention “stabilizer” and“inhibitor” have essentially the same meaning. Different inhibitors havedifferent physical characteristics and thereby functions to alter thefinal properties of the composition. For example, hydroquinone isprimarily an inhibitor for high energy free radicals; p-methoxyphenol isprimarily an inhibitor for low energy free radicals. Other free radicalinhibitors useful in the present invention include but are not limitedto butylated hydroxy toluene, butylated hydroxy anisol, ascorbic acid(vitamin C), vitamin E, beta-carotene, isoeugenol. Acids acidicinhibitors inhibit anionic polymerization and acts to control the rateof such polymerization. Such acidic inhibitors useful in the presentinvention include but are not limited to phosphoric acid, acetic acid,lactic acid, ascorbic acid, and citric acid. The preferred acidicinhibitor in the present invention is phosphoric acid.

[0059] The quantity of inhibitors used is measured in terms of parts permillion of alkyl cyanoacrylate. All of the inhibitors of the presentinvention may be used in quantities ranging from about 1 ppm to about500 ppm. For typical compositions, hydroquinone is in the range of about50 to 150 parts per million (PPM), p-methoxyphenol in the range of about50 to 150 PPM, and phosphoric acid in the range of about 125 to 375 PPM,more preferred is hydroquinone in the range of about 75 to 125 PPM,p-methoxyphenol in the range of about 75 to 125 PPM, and phosphoric acidin the range of about 187.5 to 312.5 PPM, and most preferred ishydroquinone in the range of about 95 to 105 PPM, p-methoxyphenol in therange of about 95 to 105 PPM, and phosphoric acid in the range of about50-500 PPM. Similarly, for a monomer component including of 90% n-hexylcyanoacrylate and 10% methyl cyanoacrylate, hydroquinone is in the rangeof about 50 to 150 parts per million (PPM), p-methoxyphenol is in therange of about 50 to 150 PPM, and acetic acid is in the range of about50 to 500 PPM, more preferred is hydroquinone in the range of about 75to 125 PPM, p-methoxyphenol in the range of about 75 to 125 PPM andacetic acid in the range of about 50 to 500 PPM, and most preferred ishydroquinone in the range of about 95 to 105 PPM, p-methoxyphenol in therange of about 95 to 105 PPM, and acetic acid in the range of about 150to 500 PPM.

[0060] The oligomers of the second component of the present inventionmay be prepared from any polymerizable organic monomer using anystandard oligomerization technique. To be useful in the presentinvention the oligomers must be soluble in the monomer of the firstcomponent and the plasticizer of the second component. In the presentinvention the oligomers function as viscosity modifiers and as suchcontribute to the cohesively of the compositions. The oligomers may beprepared from on or more of the same polymerizable organic monomers ofthe first component of a particular composition if this invention.Alternatively the oligomers may be prepared from monomers different fromthose used in the first component of a particular composition if thisinvention. The preferred oligomers of the second component of aparticular composition of present invention are those prepared from onethe same polymerizable organic monomers of the first component of thesame particular composition. More preferred are oligomers of alkylcyanoacrylates and most preferred are oligomers of n-hexyl cyanoacrylateand 2-hexyl cyanoacrylates.

[0061] The second component functions as an opacificant agent and apolymerization retardant. To this end, the second component includes aniodinated oil, such as Ethiodol™, or a brominated oil. Typically theiodinated oil is mixed as some percent of the total volume of the finalcomposition. The percentage solution of iodinated oil used willinfluence the polymerization rate and opacity of the composition.Generally advantageous ranges are from about 17% to 66%, preferablyabout 33%.

[0062] Alternatively, the second component can be a compositionincluding, a opacificant material, such as gold, platinum, palladium,tantalum, titanium, tungsten and barium sulfate and the like; an alkylcyanoacrylate polymer material, and an esterified fatty acid, where thefatty acids have 3 carbon atoms, for example, alkyl butyrate to 17carbons, for example, alkyl stearate, preferred are, alkyl laurate,alkyl myristate, alkyl palmatate, and alkyl stearate, most preferred isalkyl myristate, and most especially preferred is ethyl myristate. Theopacificant material is used in a fine powder form, typically, withindividual particles sized no larger than about 7 microns in diameter,preferably about 5 microns, most preferred about 2 microns and mostespecially preferred is 1 micron or smaller.

[0063] The amount of opacificant material used relative to alkylcyanoacrylate polymer will vary according to the specific materials.Factors that influence the determination of the ratio include the amountand size of the particles that are being coated by the alkylcyanoacrylate polymer. For example, for 2-hexyl cyanoacrylate and gold,2 g of 2-hexyl cyanoacrylate is used per 100 g of powdered gold(particle size of about 5±2 microns) being coated. For example, forn-hexyl cyanoacrylate and gold, 2 mg of n-hexyl cyanoacrylate is usedper 1 μm of gold at a particle size of about 2 to 10 μm, preferablyabout 0.1 to 1.0 μm , most preferably about 1 μm . The amounts varyaccordingly with the opacificant material being coated by the alkylcyanoacrylate. The alkyl cyanoacrylate and opacificant material aremechanically mixed by processing the alkyl cyanoacrylate into smallparticulate masses, and mixing with the finely powdered opacificantmaterial. The alkyl cyanoacrylate polymer coated material is then storedin a plasticizer, which serves as a medium where the alkyl cyanoacrylatepolymer coated material is maintained prior to use, and as a medium,which when contacted with the monomer component will not interfere withthe polymerization of the composition.

[0064] The characteristics of the composition of the invention can bemodified for a specific application or environment in which thecomposition is intended to be utilized. For example, changes in thelength and isomeric configuration of the alkyl side chains can alter thebrittleness of a polymer formed from a cyanoacrylate monomer. Alkylchains that result in the formation of smaller aggregates tend to beless brittle, while larger aggregates tend to be less flexible. Anothermethod of modifying the characteristics of a polymer is to use acomposition including of two or more types of alkyl cyanoacrylatemonomers in combination with the appropriate inhibitors.

[0065] For example, a composition comprised of a monomer componentincluding of 2-hexyl cyanoacrylate and phosphoric acid; and a secondcomponent including of 2-hexyl cyanoacrylate polymer, gold, and ethylmyristate results in composition A. Alternatively, a compositioncomprised of a monomer component including of 90% n-hexyl cyanoacrylateand 10% methyl cyanoacrylate, hydroquinone, p-methoxyphenol and aceticacid; and a second component including of n-hexyl cyanoacrylate polymer,gold, and ethyl myristate results in composition B

[0066] Both compositions A and B have excellent cohesion properties.When introduced into a stationary fluid, or a fluid stream in motion,such as, the lumen of a blood vessel or other like passageway, thecomposition tend to stick together to itself remaining intact as asingle mass or aggregate. This permits the polymers to be discretelydeposited or placed at the desired location without the hazard of havingpotions of the composition breaking away and depositing at undesiredlocales. Compositions A and B to have viscosity that permit theinjection of the liquid composition into a lumen of a blood vessel,duct, fistula or passageway in the body without using excessivepressure.

[0067] However, compositions A and B have different adhesion,polymerization and tactile properties. Compositions A is less adhesivethan compositions B, and its polymerization profile upon contact with ananionic environment, such as, tissue or blood, is a transition from aliquid state to a semi-solid state before completing in a soft solidstate, and the resultant polymer is a soft, flexible solid. With theseproperties Composition A is ideally suited for applications where thecomposition must penetrate further into anionic environment beforearriving at the point of final placement. A preferred use is thetreatment of arteriovenous malformations, also known as AVM. CompositionA is also ideally suited for the treatment of longer type urinaryfistulas, this is because preferred treatment requires greaterpenetration into cavity space by the liquid composition. Additionalapplications suited for Composition A are creating a tubal occlusion,and surgical adhesions. For example, a composition of the presentinvention is applied to raw intraperitoneal tissue to prevent the tissuefrom adhering to itself or other tissue.

[0068] Composition B is more adhesive than composition A, itspolymerization profile upon contact with an anionic environment, suchas, tissue or blood, is a transition from a liquid state to a soft solidand completing as a firm solid. With these properties composition B isideally suited for applications where the composition must quicklyadhere and polymerize in the surrounding anionic environment.Particularly advantageous applications for composition B is treatment ofvarious types of aneurysms.

[0069] Another advantageous application for composition B is thetreatment of fistulas, particularly those where it is desirable to havethe resultant aggregate structure form close to the point of deployment.

[0070] Still another advantageous use for composition B is for themaintenance of homeostasis during surgery, such as, during hepatectomy,renal surgery, and during gynecologic tumor surgery.

[0071] Further, composition B can be used to treat certain types ofvaricose veins, where composition B is injected into the portal vein.

[0072] The present invention is useful for filling, occluding, partiallyfilling or partially occluding an unfilled volume or space in a mass (“aspace”). In particular, the composition is useful for filling anexisting space, e.g., the lumen of a blood vessel, or the sac of ananeurysm, a space created by a transiently placed external device, e.g.,a catheter or like device, a space created by a procedure, e.g., anexcision or like procedure or implantation of an object, e.g., a stentor like device, or a space created by the composition; the compositionis also useful for adhering tissue to tissue, or adhering tissue to adevice. The composition has the property of polymerizing when it comesin contact with an anionic environment, or when it is deployed in situin an existing space, e.g., the lumen of a blood vessel, or the sac ofan aneurysm, a space created by a transiently placed external device,e.g., a catheter or like device, a space created by a procedure, e.g.,an excision or like procedure or implantation of an object, e.g., astent or like device, or a space created by the composition.

[0073] The present invention is useful as an embolic agent thatselectively creates an embolic blockage in the lumen of a blood vessel,duct, fistula or other like body passageways.

[0074] The present invention can be prepared and maintained as a firstcomponent and second component until needed or the components may becombined and stored. Storage conditions depend upon the stabilizerschosen.

[0075] The cohesive characteristics of the invention are such that whenthe composition in administered into an anionic fluid environment, suchas blood, the composition forms a single aggregate structure.Additionally, the adhesive characteristics are such that the compositionattaches to the lumen of vessel, duct, fistula or other like bodypassageways, but not to the degree where the device depositing thecomposition will become fixed to it before the practitioner can removeit.

[0076] The present invention is radiopaque. Although this characteristicis not necessary for its function as an embolic agent, radiopacityallows the embolic block to be observed with x-ray or other such imagingtechniques.

[0077] The rate of heat released during polymerization of the presentinvention is low enough such that the heat does not adversely effectsurrounding tissues that may be heat sensitive, such as brain tissue.

[0078] The present invention and its biodegradation products aresufficiently non-histotoxic and non-cytotoxic so that its presence iswell tolerated in the body.

[0079] The composition of the present invention is useful for filling,occluding, partially filling or partially occluding an unfilled volumeor space in a mass (“a space”).

[0080] The present invention provides a method for filling, occluding,partially filling or partially occluding an unfilled volume or space ina mass. The types of unfilled volumes or spaces within the scope of thepresent invention includes, but are not limited to the followinginstances.

[0081] For example, the present invention is used as a method offilling, occluding, partially filling or partially occluding an existingspace, such as, a lumen of a passageway in the body, e.g., a bloodvessel, a duct, an aneurysm, or a fistula. Examples of the typestreatments covered by this method of use, include but are not limited tothe following. The present invention is useful as a method of treatingarteriovenous malformations (AVM) where the blood vessel(s) that feedthe AVM are occluded thereby cutting off the blood supply to the AVM.The present invention is useful as a method to ablate diseased orundesired tissue by cutting off the tissue's blood supply. Inparticular, the present invention is useful as a method of treating atumor having a discrete blood supply, where the blood vessel(s) thatfeed the tumor are occluded thereby cutting off the blood supply to thetumor resulting in diminished growth or death of the tumor. The presentinvention is useful as a method of preventing or mitigating thedevelopment of an aneurysm by creating a partial occlusion at a locationin the blood vessel selected to modify the fluid dynamics within thevessel to mitigate the formation or development of an aneurysm. Thepresent invention is useful as a non-surgical method of treatingsymptomatic uterine leiomyomas by embolizing/occluding the uterineartery. This method has been reported using a non alkyl cyanoacrylatecomposition in the Journal of Vascular and Interventional Radiology,10:891-894, July-August 1999. The present invention is useful as amethod of sterilizing a female mammal by occluding the fallopian tubesthereby preventing the passage of the eggs from the ovaries to theuterus. The use of an occluding agent to sterilize a female mammal isdisclosed in U.S. Pat. No. 5,989,580 “Method of Sterilizing FemaleMammals,” herein incorporated by reference. The methods disclosed inthis patent can be advantageously applied using the compositions of thepresent invention, and are within the scope of the present invention.

[0082] The present invention is an embolic agent that provides a methodfor selectively creating and placing an embolic blockage whichmechanically blocks, totally or partially, the lumen of a blood vessel,duct, fistula or other body passageway. In particular, the currentinvention is particularly useful in blocking, totally or partially, ordiverting the flow of blood through the lumen.

[0083] The present invention can be advantageously used to block bloodflow to certain tissues or areas. For example, the present invention canbe used to treat arteriovenous malformation (AVM). An AVM is acollection of abnormal blood vessels which are neither arteries orveins. These vessels are packed closely together to form the nidus ofthe AVM. Blood flow into the AVM nidus is through thinned, enlarged,tortuous vessels and is rapidly shunted into draining veins because thenidus contains no arterioles or capillaries to provide high resistance.Clinical symptoms experienced because of AVMs are bleeding, re-directionof blood from nearby normal structures, or seizures. The primaryclinical problem associated with cerebral AVM is the potential forlethal hemorrhage. The current standard of care for treating AVMs issurgical removal, high energy radiation or embolization with particulardevices.

[0084] Further, the present invention can be used for treating cancer bydiverting or blocking blood flow to tumors, the present invention isparticularly useful for treating tumors in areas that are not easilyaccessible for surgical intervention, for example, brain tumors.

[0085] Other advantageous uses of the present invention are foraortopulmonary closure; treatment of artery pseudoaneursym; hepaticartery vascular occlusion and for temporary vascular occlusion duringco-administration of cytotoxic drugs; treatment of other types ofvessels, for example, the composition can be used for creating tubalocclusions, fallopian tube occlusions, vas deferens occlusions, andurinary occlusions.

[0086] The present invention provides a method of filling, occluding,partially filling or partially occluding a space created by atransiently placed external device, such as, a catheter balloon.Examples of the types of treatments covered by this method of useinclude, but are not limited to the following. The present invention isuseful as a method of treating an aneurysm by filling the space withinthe aneurysm with a composition of the present invention, where thecomposition polymerizes in the space within the aneurysm, therebypreventing the rupture of the aneurysm. This treatment can be practicedusing an administering means, including a means for stabilizing fluidflow distal or proximal to the body space being treated, and a means fordelivering the composition to the desired body space. An embodiment ofthe administering means is where the means for stabilizing fluid flowdistal or proximal to the body space being treated is in a first device,and the means for delivering the composition to the desired body spaceis in a second device. An embodiment of the first device includes atemporary inflatable balloon, or like structure, that is inflated tostabilize fluid flow distal or proximal to the body space to be treated,and deflated for removal after some period after the composition hasbeen delivered. Optionally the balloon structure may be juxtaposedadjacent to the body space where the composition is deposited, andinflated such that the balloon structure maintains the composition atthe body space while the composition is polymerizing, and deflated forremoval after some period after the composition has been delivered. Anembodiment of the the second device includes a catheter, or like devicefor delivering and depositing the composition of the present inventionat a desired location. Another embodiment of the administering means iswhere the means for stabilizing fluid flow distal or proximal to thebody space being treated, and the means for delivering the compositionto the desired body space are within a single device or apparatus. Suchapparatuses include, but are not limited to, catheters, catheter coils,catheter wires, catheter balloons, or like devices. Many examples ofsuch devices are known to those of ordinary skill in the art. Forexample, U.S. Pat. No. 5,795,331 “Balloon Catheter For OccludingAneurysms of Branched Vessels”, incorporated herein by reference,discloses a device and methods for delivering compositions, such asthose of the present invention. The device described combines aninflatable balloon with a catheter as a single apparatus, where theballoon is distal or proximal to the opening of the catheter. Thepresent invention has been practiced following the procedure andutilizing like devices described in Neurosurgery, Vol. 31, No. 3,September 1992, page 591 “Carotid-Cavernous Fistula Caused by a RupturedIntra-cavemous Aneurysm: Endovascular Treatment by Electrothrombosiswith Detailable Coils.” The reference describes a procedure using atemporary inflatable balloon catheter, and a catheter for placement of adetachable platinum coil. A temporary balloon occlusion is performedproximally to a fistula, and then followed by the insertion of aplatinum detachable coil into the fistula. The temporary balloonocclusion stabilizes the immediate environment near the fistula from thedisturbed flow, increased flow, turbulence, or combination thereofcreated by normal unrestricted blood flow, while a thrombus forms aroundthe platinum wire. In the present invention, a temporary balloonocclusion performs a similar function of stabilizing the immediateenvironment near the body space to be treated, for example, a fistula oraneurysm, from the disturbed flow, increased flow, turbulence, orcombination thereof created by normal unrestricted blood flow. Thetemporary balloon, optionally, may also be used to temporarily form aseal at the opening of the body space, while the composition that hadbeen deposited in the body space is polymerizing to its final form.After a period of time sufficient for the polymerization to becompleted, the temporary balloon catheter is deflated and withdrawn.

[0087] The present invention also provides a method of filling,occluding, partially filling or partially occluding a space created orresulting from a procedure, such as with the excision of tissue, orinsufflation. Examples of the types of treatments covered by this methodof use include, but are not limited to the following. The presentinvention is useful as a method of treating oozing capillaries followingan excision procedure.

[0088] The present invention further provides a method of filling,occluding, partially filling or partially occluding a space created bythe placement or implantation of an object, such as, a medical device.Examples of the types of uses covered by this method of use include, butare not limited to the following. The present invention is useful as amethod of restoring the normal fluid dynamics at the peripheral edges ofa vascular stent by filling the dead spaces between the stent and thelumen wall created by the implantation of the stent.

[0089] Still another advantageous use is the controlling and smoothingthe blood flow around stents. A major complication from the balloonangioplasty and the use of stents is disruption of the smooth flow ofblood past and around the stent which can lead to the formation of bloodclots and their associated complications. The composition of the presentinvention can be used to modify and make regular the slip streams ofblood through and adjacent to the stent to mitigate or alleviate thecause of the turbulence, and such turbulence causing states.

[0090] The present invention further provides a method of filling,occluding, partially filling or partially occluding a space created bythe composition itself, such as, where the composition is used as abulking agent. Examples of the types of uses covered by this method ofuse include, but are not limited to the following. For example, a methodof recreating normal external contours, such as following physicaltrauma.

[0091] The monomer component and second component of the presentinvention are combined just prior to use. The composition of the presentinvention is administered using any type of deployment device. The term“deployment device” refers to a device used to deploy fluids orcompositions similar to those of the present invention, such as, aneedle, catheter devices, catheter balloon, stereotaxic placementdevices, or the like. Methods for using these devices are readily knownto one of ordinary skill in the art, and such devices are commerciallyavailable. Such devices and methods are readily known to those ofordinary skill in art. For example in U.S. Pat. No. 5,925,683 “LiquidEmbolic Agents”, herein incorporated by reference, there is disclosed amethod for introducing liquid embolic agents/solutions into the humanbody to form precipitated embolic occlusion masses, and also how thismethod is used for treating hepatic tumors using portal vein embolism.In U.S. Pat. No. 5,702,361 “Method for Embolizing Blood Vessels”, hereinincorporated by reference, there is disclosed a method of embolizing avascular site in a patient's blood vessel including of introducing, viaa catheter, at the vascular site to be emobolized a non-particulateagent or a plurality of such agents, and delivering, via a catheter, tothe vascular site a polymer composition including a biocompatiblepolymer, a biocompatible solvent and contrast agent, wherein thedelivery is conducted under conditions where the polymer precipitateforms in situ at the vascular site resulting in the embolizing of theblood vessel and where the non-particulate agent is encapsulated withinthe precipitate. An administrating means can be used to deliver thecomposition of the present invention to a desired location, theadministering means including, a means for stabilizing fluid flow distalor proximal to the body space being treated, and a means for deliveringthe composition to the desired body space. An embodiment of theadministering means is where the means for stabilizing fluid flow distalor proximal to the body space being treated is in a first device, andthe means for delivering the composition to the desired body space is ina second device. An embodiment of the first device includes a temporaryinflatable balloon, or like structure, that is inflated to stabilizefluid flow distal or proximal to the body space to be treated, anddeflated for removal after some period after the composition has beendelivered. Optionally the balloon structure may be juxtaposed adjacentto the body space where the composition is deposited, and inflated suchthat the balloon structure maintains the composition at the body spacewhile the composition is polymerizing, and deflated for removal aftersome period after the composition has been delivered. An embodiment ofthe the second device includes a catheter, or like device for deliveringand depositing the composition of the present invention at a desiredlocation. Another embodiment of the administering means is where themeans for stabilizing fluid flow distal or proximal to the body spacebeing treated, and the means for delivering the composition to thedesired body space are within a single device or apparatus. Suchapparatuses include, but are not limited to, catheters, catheter coils,catheter wires, catheter balloons, or like devices. Many examples ofsuch devices are known to those of ordinary skill in the art. Forexample, U.S. Pat. No. 5,795,331 “Balloon Catheter For OccludingAneurysms of Branched Vessels”, incorporated herein by reference,discloses a device and methods for delivering compositions, such asthose of the present invention. The device described combines aninflatable balloon with a catheter as a single apparatus, where theballoon is distal to the opening of the catheter. The present inventionhas been practiced following the procedure and utilizing like devicesdescribed in Neurosurgery, Vol. 31, No. 3, September 1992, page 591“Carotid-Cavernous Fistula Caused by a Ruptured Intra-cavernousAneurysm: Endovascular Treatment by Electrothrombosis with DetailableCoils.” The reference describes a procedure using a temporary inflatableballoon catheter, and a catheter for placement of a detachable platinumcoil. A temporary balloon occlusion is performed proximally to afistula, and then followed by the insertion of a platinum detachablecoil into the fistula. The temporary balloon occlusion stabilizes theimmediate environment near the fistula from the disturbed flow,increased flow, turbulence, or combination thereof created by normalunrestricted blood flow, while a thrombus forms around the platinumwire. In the present invention, a temporary balloon occlusion performs asimilar function of stabilizing the immediate environment near the bodyspace to be treated, for example, a fistula or aneurysm, from thedisturbed flow, increased flow, turbulence, or combination thereofcreated by normal unrestricted blood flow. The temporary balloon,optionally, may also be used to temporarily form a seal at the openingof the body space, while the composition that had been deposited in thebody space is polymerizing to its final form. After a period of timesufficient for the polymerization to be completed, the temporary ballooncatheter is deflated and withdrawn.

[0092] The composition of the present invention are administered withany type of commercially available needle, catheter devices, orstereotaxic placement devices, preferably in conjunction with imagingtechnology that provides the practitioner with guidance as to theplacement of the composition. The compositions of the present inventioncan be used advantageously in conjunction with any embolization methodthat employs an embolizing agent, occluding agent, or such compositionthat creates an embolic block, or occlusion, or otherwise in effect isused for filling, occluding, partially filling or partially occluding anunfilled volume or space in a mass (“a space”). Delivery can also bemade with a micro catheter made from or coated with an agent thatlessens the likelihood of accidental gluing of the device to the vessel,for example, hydrophilic coating and silicone derivative coatings.

[0093] The following examples are given to enable those of ordinaryskill in the art to more clearly understand and to practice the presentinvention. The examples should not be considered as limiting the scopeof the invention, but merely as illustrative and representative thereof.

EXAMPLE 1

[0094] Formulation of a typical first component Material Weight (G)Moles 2-hexyl cyanoacrylate 1250 6.8964 hydroquinone 0.0764 0.000694ρ-methoxyphenol 0.0874 0.000704 phosphoric acid 0.1693 0.001726

EXAMPLE 2 Preparation of a Typical Second Component

[0095] To a Waring blender was added 0.50 G of sodium bicarbonate and250 mL water. 18 mL was added dropwise into the center of blender whilethe blender was stirring on the high setting. After the addition of wascompleted, the mixture was stirred for another minute. The resultingsolid oligomer was isolated via filtration, washed with 2 portions ofwater followed by one portion of methanol and dried in vacuo. 2.0 G ofthe this oligo (2-hexyl cyanoacrylate) was combined with 100 g ofpowdered gold and placed was placed into a standard laboratory blenderand blended for one minute. The blender was agitated constantly duringthe blending to ensure that the gold did not settle during the blending.1.020 g portions of the blended material were placed into previouslycleaned vessels and to each vessel was added 500 mg of ethyl myristateof 99.8% purity.

EXAMPLE 3 Comparison of Catheter Adhesion Force for 2-hexylCyanoacrylate and n-butyl Cyanoacrylate Compositions

[0096] This example demonstrates differences in adhesion to a catheterof an alkyl cyanoacrylate of the present invention and an n-butylcyanoacrylate.

[0097] All the mixtures were injected through a TurboTracker™ micro-catheter device (Medi-tech/Boston Scientific, Watertown, Mass.). Allmixtures were prepared immediately prior to use to prevent separation ofthe components or contamination. The catheter tips were placed at thebottom of 10 mm by 5 mm diameter wells filled with 0.2 mL of heparinizedhuman whole blood. Through the micro-catheter, 0.15 mL of each embolicmixture was injected into each well, surrounding the tip of the microcatheter. Mixtures containing n-butyl cyanoacrylate were allowed topolymerize for 1.0 minute, and those containing 2-hexyl cyanoacrylatefor 3.0 minutes. The micro-catheters were then extracted from thepolymerized cyanoacrylates at a constant rate of 8.3 mm/sec (Model 1000Materials Testing System; Instron, Canton, Mass.) and the forcesrequired for extraction were measured and recorded. (Minibeam ForceTransducer™, 25-lb capacity; Interface Advanced Force Measurement,Scottsdale, Ariz.). Five samples of each mixture were tested. Comparisonof the results was performed using the student t test. TABLE 1 Com-Alkyl Adhesion position cyanoacrylate opacificant plasticizer Force (N)1 2-hexyl 33% gold powder 20% ethyl 0.41 ± 0.14 2 2-hexyl myristate 1.00± 0.23 3 2-hexyl 33% Ethiodol ™ 0.28 ± 0.12 4 2-hexyl 50% Ethiodol ™<0.05 6 n-butyl 33% Ethiodol ™ 1.83 ± 0.21 7 n-butyl 50% Ethiodol ™ 0.34± 0.14

[0098] The data presented in table 1 clearly demonstrate that 2-hexylcyanoacrylate compositions have significantly lower adhesion to thecatheter than do the corresponding n-butyl cyanoacrylate compositions.

EXAMPLE 4 Formulation of a Monomer Component with n-hexyl Cyanoacrylateand Methyl Cyanoacrylate

[0099] A monomer component with n-hexyl cyanoacrylate is formulated withthe following materials, n-hexyl cyanoacrylate, hydroquinone,p-methoxyphenol and glacial acetic acid. The hydroquinone andp-methoxyphenol are kept under reduced pressure in a desiccator over adrying agent. The glacial acetic acid is taken up in a syringe and thesyringe and the inhibitor is weighed, an amount of glacial acetic acidadded, and the syringe with the glacial acetic acid is re-weigh todetermine the amount of glacial acetic acid that had been added. Thisprocess is repeated until the sired amount of glacial acetic acid isadded.

[0100] The monomer component is analyzed by gas chromatography forpurity under the following conditions. Instrument Description: HP5890Gas Chromatograph with HP software. chemstation Column Description:Supelco Nukol (60 meters-length, I.D., 0.32 mm, Film Thickness 1 μm)Instrument Parameters: Method 1 Injector Temperature: 220° C. DetectorTemperature: 280° C. Head Pressure: 15 PSI Air Pressure: 35 PSI HydrogenPressure: 40 PSI Aux.: 60 PSI Initial Oven Temperature: 140° C. for 20min. Ramp: 5° C./min. Final Oven Temperature: 200° C. for 50 min. ASplitless System: Injection Volume: 1.0 microliter

[0101] The component is sufficient pure if the combined impuritiespresent totals to less than 1%.

[0102] B. Following the procedures taught in Part A of the presentExample, a monomer component with a combination of methyl cyanoacrylateand n-hexyl cyanoacrylate can be made.

[0103] In place of the amount of n-hexyl cyanoacrylate called for in theabove procedure, a combination of methyl cyanoacrylate and n-hexylcyanoacrylate is use. The amounts of each material used is determinedaccording to the following ratio:

moles of methyl cyanoacrylate=0.11133 moles n-hexyl cyanoacrylate

EXAMPLE 5 Comparison of Cyanoacrylate Compositions for ConformalEndovascular Obliteration Utility

[0104] Methods and Materials

[0105] Transparent silicone models of aneurysms representing both narrowand wide neck configurations were constructed. Model A consisted of astraight 4 mm tube with three 7 mm aneurysms attached. The neck diameterwas 3 mm. Model B consisted of a helical 4 mm tubing containing fouraneurysms positioned along the greater curvature. Two were 5 mm indiameter (1 having a 2 mm neck, and the other having a 4 mm neck), andtwo were 9 mm in diameter (1 having a 3 mm neck, and the other a threeby 5 mm neck). The helical model ended in a bifurcation; a 4 mm wideneck aneurysm was positioned at the bifurcation to simulate a basilertip aneurysm.

[0106] Twelve compounded cyanoacrylates were tested, six based upon the2-hexyl cyanoacrylate/methyl cyanoacrylate monomers, six based upon the1-hexyl cyanoacrylate/methyl cyanoacrylate monomers. Additives consistedof various oils, gold for opacification, and polymerization retardants.The silicone aneurysms were filled with heparinized pig blood, and wereinjected with microcatheters under direct visualization during staticconditions, and under fluoroscopic guidance during pulsatile flowconditions.

[0107] Model A was filled with heparinized pig blood, and each of thetwelve compounds was injected into three aneurysms, directly visualizingthe degree of filing. The models were then radiographed, opened, and thecontents examined by microscopy.

[0108] Model B was perfused with heparinized pig blood, pulsatile flow,40 centimeters per second. The mixtures were introduced viamicro-catheters; injection was controlled with fluoroscopicvisualization.

[0109] All twelve compounds remained cohesive and conformed nicely tothe outline of the aneurysm. Many of the mixtures based upon the 2-hexylmonomer exhibited delayed polymerization, and could not be kept withinthe aneurysm lumen, even with adjacent balloon control of the infusionprocess. Four of the mixtures based upon the 1-hexyl monomer gave goodcohesion, good conformation, remained within the aneurysm, and allowedsome degree of angioplasty and remodeling of the arterial lumen bysilicone balloon

[0110] Although the foregoing invention has been described in somedetail by way of illustration and example for purposes of clarity andunderstanding, it will be apparent to those of ordinary skill in the artin light of the teaching of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the claims.

What is claimed is:
 1. A composition comprising a first component and asecond component, wherein the first component includes at least twopolymerizable organic monomers, and wherein the second componentincludes an oligomer of a polymerizable organic monomer, a plasticizer,and an opacificant agent, wherein the composition polymerizes uponcontact with an anionic environment.
 2. The composition according toclaim 1, wherein at least one of said polymerizable organic monomers isan alkyl cyanoacrylate.
 3. The composition according to claim 2, whereinboth of said polymerizable organic monomers are alkyl cyanoacrylates. 4.The composition according to claim 2, wherein said alkyl cyanoacrylatesare chosen such that the alkyl chain contains from 1 to 18 carbon atoms.5. The composition according to claim 2, wherein said cyanoacrylates areselected from methyl cyanoacrylate, n-butyl cyanoacrylate, isobutylcyanoacrylate, n-hexyl cyanoacrylate, 2-hexyl cyanoacrylate, n-octylcyanoacrylate, or 2-ethylhexyl cyanoacrylate.
 6. The compositionaccording to claim 1, wherein said first component includes at least onepolymerization inhibitor.
 7. The composition according to claim 6,wherein said inhibitors act primarily to inhibit free radicalpolymerization.
 8. The composition according to claim 7, wherein saidinhibitors are present in the range of about 1 to 500 parts per million.9. The composition according to claim 6, wherein at least one of saidinhibitors acts primarily to inhibit anionic polymerization.
 10. Thecomposition according to claim 9, wherein said inhibitor is an acid. 11.The composition according to claim 10, wherein said acid is present inthe range of about 50 to 500 parts per million.
 12. The compositionaccording to claim 11, wherein said acid is acetic acid or phosphoricacid.
 13. The composition according to claim 12, wherein said aceticacid or phosphoric acid is present in the range of about 200 to 300parts per million.
 14. The composition according to claim 1, whereinsaid plasticizer is an esterified fatty acid.
 15. The compositionaccording to claim 14, wherein said esterified fatty acids are chosenfrom the group consisting of laurates, palmitates, oleates, myristates.or stearates
 16. The composition according to claim 15, wherein saidesterified fatty acid is ethyl myristate.
 17. The composition accordingto claim 1, wherein said opacificant agent is a metal.
 18. Thecomposition according to claim 17, wherein said metal is selected fromgold, platinum, palladium, tantalum, titanium, or mixtures and alloysthereof.
 19. The composition according to claim 18, wherein said metalis gold.
 20. The composition according to claim 19, wherein said gold isin fine powder form with individual particles no larger than about 7microns in diameter.
 21. The composition according to claim 20, whereinsaid gold is in fine powder form with individual particles no largerthan about 5 microns in diameter.
 22. The composition according to claim21, wherein said gold is in fine powder form with individual particlesno larger than about 2 microns in diameter.
 23. The compositionaccording to claim 22, wherein said gold is in fine powder form withindividual particles no larger than about 1 micron in diameter.
 24. Acomposition comprising a first component and a second component, saidfirst component comprising n-hexyl cyanoacrylate, methyl cyanoacrylateand phosphoric acid, said second component comprising an oligomer ofn-hexyl cyanoacrylate, ethyl myristate, and gold, wherein saidcomposition polymerizes upon contact with an anionic environment. 25.The composition according to claim 24, wherein said second componentfurther includes a halogenated oil.
 26. The composition according toclaim 25, wherein said halogenated oil is iodinated castor oil.
 27. Amethod of filling, occluding, partially filling, or partially occludingan unfilled volume or space in an anionic environment, said methodcomprising administering a composition comprising a first component anda second component, wherein said first component includes at least twopolymerizable organic monomers, and wherein said second componentincludes an oligomer of a polymerizable organic monomers, plasticizer,and an opacificant agent, wherein said composition polymerizes uponcontact with said anionic environment when administered with a devicecomprising a means for stabilizing fluid flow distal or proximal to saidspace and a means for delivering said composition to said space, wherebysaid space is filled, occluded, partially filled, or partially occluded.28. The method according to claim 27, wherein said stabilizing means anddelivering means are within one device.
 29. The method according toclaim 27, wherein said stabilizing means is in a first device, and saiddelivering means is in a second device.
 30. The method according toclaim 27, wherein said space is an existing space in human or animalbody.
 31. The method according to claim 30, wherein said existing spaceis created by a transiently placed external device.
 32. The methodaccording to claim 30, wherein said existing space is created by orresulting from a procedure.
 33. The method according to claim 30,wherein said existing space is created by the placement or implantationof an object.
 34. The method according to claim 30, wherein saidexisting space is created by the composition itself.
 35. The methodaccording to claim 30, wherein said existing space is a lumen of apassageway in the human body.
 36. The method according to claim 30,wherein said existing space is a blood vessel.
 37. The method accordingto claim 30, wherein said existing space is a duct.
 38. A method forablating diseased or undesired tissue, said method comprisingadministering a composition according to claim 1 to blood vessel(s) thatfeed said tissue, whereby said blood vessel(s) are occluded, therebycutting off blood supply to said tissue, whereby said diseased orundesired tissue is ablated.
 39. The method according to claim 38,wherein said undesired tissue is an arteriovenous malformation.
 40. Themethod according to claim 38, wherein said undesired tissue is a tumor.41. The method according to claim 38, wherein said undesired tissue isan uterine leiomyoma.
 42. A method for treating arteriovenous venousmalformation (AVM) by cutting off the blood supply to said AVM, saidmethod comprising administering a composition according to claim 1 toblood vessel(s) that feed said AVM, whereby said blood vessel(s) areoccluded, thereby cutting off blood supply to said AVM, whereby said AVMis treated.
 43. A method for treating a tumor by cutting off the bloodsupply to said tumor, said method comprising administering a compositionaccording to claim 1 to blood vessel(s) that feed said tumor, wherebysaid blood vessel(s) are occluded, thereby cutting off blood supply tosaid tumor, whereby said tumor is treated.
 44. A method for treating auterine leiomyoma by cutting off the blood supply to said leiomyoma,said method comprising administering a composition according to claim 1to blood vessel(s) that feed said leiomyoma, whereby said bloodvessel(s) are occluded, thereby cutting off blood supply to saidleiomyoma, whereby said uterine leiomyoma is treated.
 45. A method forsterilizing a female mammal, said method comprising administering acomposition according to claim 1 to the fallopian tubes of said femalemammal thereby preventing passage of eggs from the ovaries to the uterusof said female mammal, whereby said female mammal is sterilized.
 46. Amethod of filling, occluding, partially filling, or partially occludingan unfilled volume or space in an anionic environment, said methodcomprising administering a composition comprising a first component anda second component, wherein said first component includes at least twopolymerizable organic monomers, and wherein said second componentincludes an oligomer of a polymerizable organic monomer, a plasticizer,and an opacificant agent, wherein said composition polymerizes uponcontact with said anionic environment when administered with a devicecomprising a temporary inflatable balloon and a catheter, whereby saidspace is filled, occluded, partially filled, or partially occluded. 47.A method for controlled delivery of a therapeutic, chemotherapeutic, orradiation delivery device, to a desired location in the human body, saidmethod comprising combining said therapeutic, chemotherapeutic, orradiation delivery device with a composition according to claim 1, anddelivering said combination to said desired location, whereby saidtherapeutic, chemotherapeutic, radiation delivery device, or genetherapy composition is gradually released at said desired location inthe human body.
 48. A method for delivering magnetic particles to alocation in a mammalian body, said method comprising combining saidmagnetic particles with a composition according to claim 1, anddelivering said combination to said location.
 49. A method for adheringa first section of mammalian tissue to a second section of mammaliantissue, said method comprising contacting said first tissue with acomposition according to claim 1, and contacting said second tissue withsaid first tissue, whereby said first tissue is adhered to said secondtissue.
 50. A method for adhering a section of mammalian tissue to anon-tissue surface, said method comprising contacting said tissue with acomposition according to claim 1, and contacting said non-tissue surfacewith said section of mammalian tissue, whereby said tissue is adhered tosaid non-tissue surface.
 51. The method according to claim 50, whereinsaid non-tissue surface is a medical device.
 52. The method according toclaim 51, wherein said medical device is a venous valve, a heart valve,or a stent.
 53. A method for delivering a composition according to claim1 to a location in a mammalian body, said method comprisingadministering said composition with a device comprising a means forstabilizing fluid flow distal or proximal to said location, and a meansfor delivering said composition, whereby said composition is deliveredto said location.